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Methods of diagnosing and treating pre-eclampsia or eclampsia

a technology of eclampsia and edema, which is applied in the direction of dna/rna fragmentation, depsipeptides, peptide/protein ingredients, etc., can solve the problems of cerebral edema and seizures seen in eclampsia

Active Publication Date: 2005-02-03
BETH ISRAEL DEACONESS MEDICAL CENT INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0010] In a related aspect, the invention provides a method of treating or preventing pre-eclampsia or eclampsia in a subject by administering to the subject a compound (e.g., nicotine, theophylline, adenosine, nifedipine, minoxidil, or magnesium sulfate) that increases the level of a growth factor capable of binding to sFlt-1, where the administering is for a time and in an amount sufficient to treat or prevent pre-eclampsia or eclampsia in a subject.

Problems solved by technology

Excess sFlt-1 may also lead to eclampsia by disrupting the endothelial cells that maintain the blood-brain barrier and / or endothelial cells lining the choroids plexus of the brain thus leading to cerebral edema and the seizures seen in eclampsia.

Method used

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  • Methods of diagnosing and treating pre-eclampsia or eclampsia
  • Methods of diagnosing and treating pre-eclampsia or eclampsia
  • Methods of diagnosing and treating pre-eclampsia or eclampsia

Examples

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example 1

[0098] Increased Levels of sFlt-1 mRNA and Protein in Pregnant Women with Pre-eclampsia.

[0099] In an attempt to identify novel secreted factors playing a pathologic role in pre-eclampsia, we performed gene expression profiling of placental tissue from women with and without pre-eclampsia using Affymetrix U95A microarray chips. We found that the gene for sFlt-1 was upregulated in women with pre-eclampsia.

[0100] In order to confirm the upregulation of sFlt-1 in pre-eclampsia, we performed Northern blots to analyze the placental sFlt-1 mRNA levels (FIG. 1A) and ELISA assays to measure serum protein levels of sFlt-1 (FIG. 1B) in pre-eclamptic pregnant women as compared with normotensive pregnant women. Pre-eclampsia was defined as (1) a systolic blood pressure (BP)>140 mmHg and a diastolic BP>90 mmHg after 20 weeks gestation, (2) new onset proteinuria (1+ by dipstik on urinanalysis, >300 mg of protein in a 24 hour urine collection, or random urine protein / creatinine ratio>0.3, and (3)...

example 2

[0103] Serum from Women with Pre-eclampsia Inhibits Angiogenesis in an in vitro Endothelial Tube Assay.

[0104] We hypothesized that excess circulating sFlt-1 in patients with pre-eclampsia causes endothelial dysfunction and leads to an anti-angiogenic state. To address this, we used an endothelial tube assay as an in vitro model of angiogenesis. Growth factor reduced Matrigel (7 mg / mL, Collaborative Biomedical Products, Bedford, Mass.) was placed in wells (100 μl / well) of a pre-chilled 48-well cell culture plate and incubated at 37° C. for 25-30 minutes to allow polymerization. Human umbilical vein endothelial cells (30,000+ in 300 μl of endothelial basal medium with no serum, Clonetics, Walkersville, Md.) at passages 3-5 were treated with 10% patient serum, plated onto the Matrigel coated wells, and incubated at 37° C. for 12-16 hours. Tube formation was then assessed through an inverted phase contrast microscope at 4× (Nikon Corporation, Tokyo, Japan) and quantitatively analyzed (...

example 3

[0106] sFlt-1 Inhibits VEGF and PlGF Induced Vasodilation of Renal Microvessels.

[0107] The causative role of sFlt-1 in vasoconstriction was determined using an in vitro microvascular reactivity experiment. Microvascular reactivity experiments were done as described previously using rat renal microvessels (Sato et al., J. Surg. Res., 90:138-143, 2000). Kidney artery microvessels (70-170 μm internal diameter) were dissected from rat kidneys using a 10× to 60× dissecting microscope (Olympus Optical, Tokyo, Japan). Microvessels were placed in an isolated microvessel chamber, cannulated with dual glass micropipettes measuring 30-60 μm in diameter, and secured with a 10-0 nylon monofilament suture (Ethicon, Somerville, N.J.). Oxygenated (95% oxygen and 5% carbon dioxide) Krebs' buffer solution warmed to 37° C. was continuously circulated through the vessel chamber and a reservoir containing a total of 100 ml of the solution. The vessels were pressurized to 40 mmHg in a no-flow state usin...

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Abstract

Disclosed herein are methods for diagnosing pre-eclampsia and eclampsia. Also disclosed herein are methods for treating pre-eclampsia and eclampsia using compounds that increase VEGF or PlGF levels or compounds that decrease sFlt-1 levels. Compounds that inhibit the binding of VEGF or PlGF to sFlt1- are also disclosed herein for the treatment of pre-eclampsia or eclampsia.

Description

CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation-in-part of U.S. patent application Ser. No. 10 / 624,809, filed Jul. 21, 2003, which claims the benefit of U.S. Provisional Application Nos. 60 / 397,481, filed on Jul. 19, 2002; 60 / 451,796, filed on Mar. 3, 2003; and 60 / 467,390 filed on May 2, 2003, herein incorporated by reference.FIELD OF THE INVENTION [0002] In general, this invention relates to the detection and treatment of subjects having pre-eclampsia or eclampsia. BACKGROUND OF THE INVENTION [0003] Pre-eclampsia is a syndrome of hypertension, edema, and proteinuria that affects 5 to 10% of pregnancies and results in substantial maternal and fetal morbidity and mortality. Pre-eclampsia accounts for at least 200,000 maternal deaths worldwide per year. The symptoms of pre-eclampsia typically appear after the 20th week of pregnancy and are usually detected by routine ing of the woman's blood pressure and urine. However, these monitoring methods are in...

Claims

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Application Information

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IPC IPC(8): A61K31/522C07K16/12C07K16/28C12Q1/48G01N33/68G01N33/74
CPCA61K31/522C12N2310/14C07K16/1217C07K16/18C07K16/2863C07K16/40C12Q1/485G01N33/689G01N33/6893G01N33/74G01N2500/00G01N2800/368A61K38/1866A61K38/1891C12N15/1138C12N2310/11A61K2039/505A61P15/00A61K39/3955A61K45/06C07K2317/76
Inventor KARUMANCHI, S. ANANTHMAYNARD, SHARONSUKHATME, VIKAS P.
Owner BETH ISRAEL DEACONESS MEDICAL CENT INC
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